Intracellular Survival of Leishmania major Depends on Uptake and Degradation of Extracellular Matrix Glycosaminoglycans by Macrophages

PLoS Pathogens

Joanne Heng¹  Malcolm J. McConville¹  Tracey J. Brown²  Eleanor C. Saunders³  Thomas Naderer³  Joachim Kloehn³  Thusitha W. Rupasinghe³ 

[1] Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia;Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia;The Department of Biochemistry and Molecular Biology and the Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia

关键词: Macrophages;    Promastigotes;    Parasitic diseases;    Amastigotes;    Leishmania;    Lesions;    Chitin;    Extracellular matrix;   

DOI  :  10.1371/journal.ppat.1005136

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Leishmania parasites replicate within the phagolysosome compartment of mammalian macrophages. Although Leishmania depend on sugars as a major carbon source during infections, the nutrient composition of the phagolysosome remains poorly described. To determine the origin of the sugar carbon source in macrophage phagolysosomes, we have generated a N-acetylglucosamine acetyltransferase (GNAT) deficient Leishmania major mutant (∆gnat) that is auxotrophic for the amino sugar, N-acetylglucosamine (GlcNAc). This mutant was unable to grow or survive in ex vivo infected macrophages even when macrophages were cultivated in presence of exogenous GlcNAc. In contrast, the L. major ∆gnat mutant induced normal skin lesions in mice, suggesting that these parasites have access to GlcNAc in tissue macrophages. Intracellular growth of the mutant in ex vivo infected macrophages was restored by supplementation of the macrophage medium with hyaluronan, a GlcNAc-rich extracellular matrix glycosaminoglycan. Hyaluronan is present and constitutively turned-over in Leishmania-induced skin lesions and is efficiently internalized into Leishmania containing phagolysosomes. These findings suggest that the constitutive internalization and degradation of host glycosaminoglycans by macrophages provides Leishmania with essential carbon sources, creating a uniquely favorable niche for these parasites.

【 授权许可】

CC BY